Adjuvant therapy represents a complementary approach to vaccines and conventional anti-microbial drugs as countermeasures against infectious disease. Adjuvants target and enhance innate host defenses, which have evolved over millennia to counter a wide spectrum of infectious agents. They also enhance downstream adaptive immune responses. Toll-like receptor (TLR) agonists represent the best-defined innate adjuvants, and some are under clinical testing. However, data from many studies suggest that other innate receptors may serve as alternative targets for such drugs. In ongoing adjuvant discovery programs, we have identified adjuvant activity in plant polysaccharides and alkaloids and unique synthetic compounds. In our first RCE project, we found that Coxiella burnetii i.p. infection in BALB/c mice is responsive to adjuvant therapy. In this renewal, we intend to test the effectiveness of plant derived agonists and synthetic compounds to 1) enhance innate resistance against C. burnetii infection, and 2) augment downstream adaptive immune responses against antigens and vaccine preparations." We also plan on expanding our adjuvant discovery efforts to include testing partially purified extracts of Mycobacterium tuberculosis and Burkholderia pseudomallei. The hypothesis to be tested is: Adjuvant therapy represents an effective countermeasure against C. burnetii infection. The following Specific Aims will be pursued: Specific Aim 1. Development of plant polysaccharides and alkaloids (securinine) as innate agonists to enhance innate resistance against C. burnetii infection and augment vaccine responses. Specific Aim 2. Development of novel synthetic compounds that target N-formyl peptide receptors to enhance innate resistance against C. burnetii infection and augment vaccine responses. Specific Aim 3. New adjuvant discovery focused on screening immunomodulatory compounds derived from Mycobacterium and Burkholderia. This research project fits within the RMRCE Integrated Research Focus on Immunomodulation, Adjuvants and Vaccines, and will interact directly with RP1.1 and RP1.2, and utilize the resources of Cores B, D and F. It also represents a direct collaboration between MSU and CSU investigators in efforts to identify novel adjuvant materials. Finally, this project is relevant to all infection models being pursued in the RMRCE in the context of new vaccine and/or therapeutic adjuvant discovery.